Biomolecular Machines

Discussion in 'Biology & Genetics' started by Techne, Oct 7, 2008.

  1. Techne Registered Senior Member

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    211

    A thread to lump together all the interesting discoveries regarding the intracellular biomolecular machinery that are crucial for life to exist. Please post interesting discoveries and perhaps describe the functionality of these intracellular biomolecular machines.

    Intracellular biomolecular machinery include the following:
    1) DNA replication and repair machinery (replisome)
    2) DNA transcription machinery and RNA processing and translation machinery (Spliceosomes and ribosomes)
    3) Cell cycle signaling network (pRB, e2F, CDKs)
    4) Programmed cell death machinery (Apoptosis, autophagy, mitotic catastrophe)
    5) Protein processing machinery (Chaperones, ubiquitin-proteasome system)
    6) Intracellular signaling networks (protein kinases and phosphatases)
    7) Mechanical machines for intracellular shuttling of biomolecules and cellular movement (Microtubule network, kinesin, dynein)
    8) Energy production machines (Electron transport chain, F0F1 ATP synthase)


    The Replisome: Sliding clamps, clamp-loaders and helicases.​

    Sliding clamps are ring-shaped proteins that some refer to as the “guardians” of the genome or others name them as the “ringmasters” of the genome.
    Interestingly these clamps are structurally and functionally conserved in all branches of life and crystallographic studies have shown that they have almost superimposable three-dimensional structures, yet these components have very little sequence similarity (Figure 1) [1].

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    Figure 1: Sliding clamps from the various domains of life.​

    The picture below is taken from the Molecular Biology Visualization of DNA video (2:14) from the freesciencelectures.com site.
    Great video!

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    Figure 2: Replication machinery.​

    The following components can be seen:
    Sliding clamps (PCNA in eukaryotes): Green circular shaped
    Clamp loader (RFC in eukaryotes): Blue-white component in the middle
    (Figure 3: Structures of PCNA connected to RFC (front))

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    (Figure 4: Structures of PCNA connected to RFC (side))​

    (Figure 5: Structures of PCNA connected to RFC (back))
    Helicase: Blue (Figure 6: Helicase (front))
    DNA polymerase: Dark-blue components attached to the sliding clamps
    Primase: Green component attached to helicase
    Leading strand: Spinning off to the right
    Lagging strand: Spinning off to the top

    They are not ringmasters for nothing.
    Sliding clamps participate and control events that orchestrate DNA replication events in the following ways:
    • Enhancement of DNA polymerase activity.
    • Coordinate Okazaki fragment processing.
    • Prevention of rereplication
    • Translesion synthesis
    • Prevents sister-chromatid recombination and also coordinates sister-chromatid cohesion
    • Crucial role in mismatch repair, base excision repair, nucleotide excision repair
    • Participates in chromatin assembly

    Other functions include:
    • Epigenetic inheritance
    • Chromatin remodeling
    • Controls cell cycle and cell death signaling

    The true ringmasters.

    Clamp loaders are another group of interesting proteins (see video and figures 3-5 above). Interestingly again, their functional and structural architecture are conserved across the three domains of life with low-level sequence similarity [2]. At the replication fork during replication, they load the sliding clamps many times onto the lagging strand (after DNA priming) and only once onto the leading strand. They also act as a bridge to connect the leading and lagging strand polymerases and the helicase. Which brings us to another interesting group of proteins; the helicases.

    Helicases are also known to be ring-shaped motor proteins, typically hexamers (see figure 6) and separate double-stranded DNA into single-stranded templates for the replication machinery. Replication occurs at about 1000 base pairs per second due to the highly efficient combination of sliding clamps and the polymerases. Thus, helicases need to unwind DNA at at least that speed. Unwinding DNA too slowly and the replication machinery might break down . Unwind the DNA too fast or untimely and harmful mutations might occur as single-stranded DNA is prone to degradation and cytosine deamination.

    The speed at which helicase unwinds DNA is no accident though, as it is intrinsically controlled. As helicase is bound to the lagging strand, it unwinds the leading strand in a separate direction. Applying a pulling force on the leading strand leads to a 7-fold increase in the speed of DNA unwinding by helicase [3, 4]. The highly efficient DNA polymerase/sliding clamp combination provides this controlling force on the leading strand. This forms a robust unwinding/polymerization interaction whereby polymerization controls and prevents unwanted DNA unwinding.

    Altogether, the replisome machinery provide a robust way for DNA replication to prevent unnecessary DNA damage and mutation.

    References.
    1. Vivona JB, Kelman Z. The diverse spectrum of sliding clamp interacting proteins. FEBS Lett. 2003 Jul 10;546(2-3):167-72.
    2. Jeruzalmi D, O'Donnell M, Kuriyan J. Clamp loaders and sliding clamps. Curr Opin Struct Biol. 2002 Apr;12(2):217-24.
    3. Ha T. Need for speed: mechanical regulation of a replicative helicase. Cell. 2007 Jun 29;129(7):1249-50.
    4. Johnson DS, Bai L, Smith BY, Patel SS, Wang MD. Single-molecule studies reveal dynamics of DNA unwinding by the ring-shaped T7 helicase. Cell. 2007 Jun 29;129(7):1299-309.
     
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  3. Techne Registered Senior Member

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    Something related to the replisome and DNA repair:
    DNA Repair: Structure Of The Mre11 Protein Bound To DNA

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    Small-angle x-ray scattering confirmed the U-shape of the Mre11 dimer (gray envelope) in solution. Although of lower resolution than crystallography, SAXS was used to establish the orientation of the dimer's components, as shown in ribbon format. (Credit: Image courtesy of DOE/Lawrence Berkeley National Laboratory)​




    Something related to the movement of cells:
    Landmark Discovery Of 'Engine' That Drives Cell Movement
    Emphasis mine.
    Hard work with spectacular results

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    Last edited: Oct 7, 2008
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  5. Techne Registered Senior Member

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    Using Living Cells As Nanotechnology Factories


    Cells Coordinate Gene Activity With FM Bursts, Scientists Find




    Proteins Have Controlled Motions, Researcher Shows


    So much control, all the way down to protein motion.

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  7. Techne Registered Senior Member

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    Robustness and back-up systems​

    New Evidence On The Robustness Of Metabolic Networks

    You Can Be Replaced: Immune Cells Compensate For Defective DNA Repair Factor


    Preadaptations are good for the future.

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    Newly discovered mechanics of a molecular machine that transports proteins.


    Channel hopping: protein translocation through the SecA–SecY complex
    Research articles:
    Structure of a complex of the ATPase SecA and the protein-translocation channel
    A role for the two-helix finger of the SecA ATPase in protein translocation
    Conformational transition of Sec machinery inferred from bacterial SecYE structures
    Exquisite control of biomolecular processes with the aid of nanomachines all the way down to the simplest organisms

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  8. Techne Registered Senior Member

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    Paley’s Watch?​

    Cyanobacteria are one of the organisms with the deepest history, with evidence of their remains dating back possibly to about 3.5 billion years ago. So, what is found in some of these simple cells? CLOCKWORK...

    A cyanobacterial circadian clockwork.
    On the structure of:
    Structural Insights into a Circadian Oscillator
    A biological clock with all the cogs and gears. The KaiABC clock is a bona fide dynamically oscillating nanomachine that precess unidirectionally and robustly. Present in one of the most primitive, simple organisms...


    More on the nanomachinery that governs DNA processing.
    Biologists Discover Motor Protein That Rewinds DNA
    Clocks, motors, nanomachines etc. Superbly intelligent biomolecular machinery making life possible.

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  9. Techne Registered Senior Member

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    A little about RNA splicing machinery: Possibly the most complex macromolecular machine in the cell


    What is RNA splicing?
    Many human genes (+-94%) contain exons (the DNA sequences that code for amino acids). These exons can be spliced together to form different types of proteins from a single gene.


    How is it controlled?
    Extensively and exquisitely controlled.


    How common is it in humans?
    Human Genes: Alternative Splicing Far More Common Than Thought
    Thus, the same gene can result in different functions, depending on the functionality and control of the RNA splicing machinery.


    Is it important?
    Humans And Chimps Differ At Level Of Gene Splicing
    Not only do we differ genetically, but the way the genes are processed differ.


    What happens if the machinery malfunctions?
    Quality control systems are in place.
    RNA Biology Finding Makes Waves By Challenging Current Thinking
    Present in yeast, primitive organisms

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    But how prevalent is this kind of machinery?
    Visualizing The Machinery Of mRNA Splicing
    Forms of this machinery present all the way down to bacteria

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    .



    Here is a video describing the process.
     
  10. Techne Registered Senior Member

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    How 'molecular machines' kick start gene activation revealed

    The "melting out" process is carried out by helicases which is part of the replisome. Exquisitely controlled.
    Helicases are also known to be ring-shaped motor proteins, typically hexamers and separate double-stranded DNA into single-stranded templates for the replication machinery. Replication occurs at about 1000 base pairs per second due to the highly efficient combination of sliding clamps and the polymerases. Thus, helicases need to unwind DNA at at least that speed. Unwinding DNA too slowly and the replication machinery might break down . Unwind the DNA too fast or untimely and harmful mutations might occur as single-stranded DNA is prone to degradation and cytosine deamination. The speed at which helicase unwinds DNA is no accident though, as it is intrinsically controlled. As helicase is bound to the lagging strand, it unwinds the leading strand in a separate direction. Applying a pulling force on the leading strand leads to a 7-fold increase in the speed of DNA unwinding by helicase. The highly efficient DNA polymerase/sliding clamp combination provides this controlling force on the leading strand. This forms a robust unwinding/polymerization interaction whereby polymerization controls and prevents unwanted DNA unwinding.

    So machines govern the activity of gene expression, and machines are governed by gene expression through a reasonably optimal genetic code mmmm....:cheers:
     
  11. Techne Registered Senior Member

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    211
    How long will a reaction take to complete without enzymes?
    Well, some reactions will only complete in about 2.3 billion years without them...
    Without Enzyme, Biological Reaction Essential To Life Takes 2.3 Billion Years

    But enzymes don't just pop into existence, not even under the BEST pre-biotic synthesis scenarios. Enzymes are produced and folded into the correct conformation by.... other enzymes... controlled by.... biomolecular machines and a reasonably optimal genetic code...

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    More about the efficiency of enzymes:
    Biochemistry: Enzymes under the nanoscope
    Enzymes are guided into their correct 3D configuration by other enzyme complexes known as chaperones (part of the heat-shock protein family). What happens if the configurations are not right? Scientists determined that some enzymes, as in the case of ketosteroid isomerase, are so precisely folded for their particular ligand/substrate that if it the 3d conformation was off by even 10 picometers (10^12 meters) it would lose its efficiency. Firstly, the conformation has to be just right to tightly bind the ligand into the pocket of the protein, then another mechanism (built in property of the enzyme) is responsible the transfer of electrons in order to catalyze and complete the enzymatic reaction. Our current best efforts at designing artificial enzymes are (from the article) “still tens of billions of times smaller than those of many enzymes.”

    The ribosome is a super complex of enzymes, a molecular machine responsible for the building of polypeptide chains which in turn are folded into active proteins by chaperone complexes.
    Problems do occur, but checks and balances are present. For example:
    Side-chain recognition and gating in the ribosome exit tunnel
    At the exit tunnel of the ribosome, it is hypothesized that there are gate and latch mechanisms with active valves controlling the exit of polypeptides. The researchers conclude that these mechanisms play a role in the regulation of "nascent chain exit and ion flux". Sort-off like a final checkpoint.

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    As already seen, without enzymes, reactions that are crucial to life might take billions of years to complete. Small changes (10 picometers) in the 3D structure of an enzyme can also negatively affect the function of an enzyme.
    So how are enzymes folded into their active conformation?


    Chaperonins: Two-stroke, two-speed, protein machines

    Article:
    Setting the chaperonin timer: A two-stroke, two-speed, protein machine
    From the article:


    Partial part and dynamics of the system.
    Nice video of how it operates

    Machines folding machines into place. Beautiful... :cheers:
     
  12. Techne Registered Senior Member

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    211
    The kinesin motor machine:
    Nice pic

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    How Tiny Cell Proteins Generate Force To 'Walk'
    Microtubules, quantum physics, and consciousness? They form tracks for neurotransmitters to be transported and can possibly act as quantum computational structures. Also, see the mice below.

    Few videos describing the motor:
    Kinesin Transport Protein
    Kinesin Explanation

    Mice with a few kinesin mutations? Look like there is something wrong with their neurphysiology, almost like they are not interacting with the environment in the correct way?
    Kinesin mutations in mice

    Ever wondered how cellular machinery causes replication of cells?
    Awesome video:
    Inside the cell
    And it does not even remotely cover the intricate mechanisms controllong the process.

    Another video of mitosis:
    Mitosis
    Active cyclinB/cdc2 plays a part in nuclear envelope breakdown, and destruction of cyclinB and abolition of cdc2 activity allows nuclear envelope formation.

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    In real life it looks something like this:

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  13. Techne Registered Senior Member

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    More machines and clockwork:
    Clockwork That Drives Powerful Virus Nanomotor Discovered

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    Related article:
    Biologists Learn Structure, Mechanism Of Powerful 'Molecular Motor' In Virus

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    Again, taking clues from cellular machinery to design our own optimal nanotechnology.


    So we think we have designed GPS systems?
    Primary Cilium As Cellular 'GPS System' Crucial To Wound Repair
    Purposefully communicating information as a means to an end... wound healing.

    Faulty Darwinian reasoning leading to faulty conclusions only to be corrected by scientific inquiry...
     
  14. Techne Registered Senior Member

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    211
    The structures that life depend on are representations based on the rules of energy and information. Energy can be argued to supervene on information, and cells can use energy to manipulate information. These processes depend on these structures and functions.

    How The Sensory Organs Of Bacteria Function
    So, bacteria forms a picture of their surroundings so they can adequately respond to the environment.

    And cells seem to count as well.

    How Do Cells Count? Scientists Take A Step Further In Unraveling Mystery Of How Cells Control Number Of Centrosomes

    Sensing, counting and manipulating information in order to control succesful self-replication. Exquisitely controlled

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    New Protein Function Discovered Related article: New Protein Function Discovered; Sheds Light On Intricate Mechanics Of Cell Division

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    Nucleotide-binding Oligomerization Domain (NOD)

    Original article:
    ATPase Cycle of the Nonmotile Kinesin NOD Allows Microtubule End Tracking and Drives Chromosome Movement
     
  15. Techne Registered Senior Member

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    211
    Yes, photosynthesis coupled with quantum mechanics is a fascinating subject.
    Very nice article about the photosynthesis photosystem II mechanism and how design principles of the system can be used to engineer similar systems to produce solar fuel.

    Solar water-splitting into H2 and O2: design principles of photosystem II and hydrogenases


    Emphasis mine.

    Also, the photosystem II mechanism makes use of quantum mechanical computing principles, leading to an excellent quantum efficiency for water-splitting.

    From Nature;Vol 446;12 April 2007: Quantum path to photosynthesis
    And in the same issue: Evidence for wavelike energy transfer through quantum coherence in photosynthetic systems

    A glimpse into the future of our own designs

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  16. Walter L. Wagner Cosmic Truth Seeker Valued Senior Member

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    Techne:

    Thanks for the fascinating links and information.
     
  17. Techne Registered Senior Member

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    And quantum physics and consciousness? Think there could be a link?

    Quantum physics and Consciousness. Are they connected? The microtubule connection.

    Research into the brain-body-mind problem is ongoing and one way of attempting to understand it is to try and describe consciousness in terms of material particles and fields interacting between inputs, internal states, and outputs without any intrinsic meaning. Terms such as “feeling”, “intention”, “knowing” and “choice” are thus not viewed as primary causal factors of consciousness, but a byproduct of these blind interactions.

    Quantum physics has not been at the forefront to attempt to describe consciousness as the neurocomputational model of laterally connected input layers of the brain’s neurocomputational architecture is viewed as the most credible explanation for consciousness. One problem that quantum mechanics face is the effect of quantum decoherence (The Role of Decoherence in Quantum Mechanics) and failures to measure it. Essentially, quantum states are believed to be too sensitive and fragile to disruption by thermal energy to affect the macroscopic nature of proteins and other macromolecular structures.

    The Penrose-Hameroff orchestrated objective reduction (orch. OR) model provides a basis to connect consciousness with quantum mechanics. Microtubules are integral in this theory.

    Connecting quantum mechanics, aromatic ring pi-bonds, protein formation, microtubules and consciousness.

    The “quantum physics” and “aromatic ring pi bond” connection.
    An aromatic (aromaticity) compound is composed of a conjugated planar ring system with delocalized pi electron clouds. Benzene is an example of an aromatic compound (Figure 1). In benzene (and other aromatic compounds) the double bonds are shorter than the single bonds, causing the carbon atoms to be pulled and pushed between two states and thus vibrate between two states (Figure 2). The pi electrons are also delocalized above and below the carbon ring (Figure 1). Aromatic compounds are thus described to be resonating and are best described quantum mechanically.

    The “aromatic ring pi bond” and “protein formation” connection.
    4 amino acids contain aromatic rings: tyrosine, phenylalanine, tryptophan and histidine (Figure 3). Histidine, however has 6 delocalized electrons but not a benzene ring and is hydrophilic (more polar).

    When peptide chains fold to form proteins, the structure is stabilized and dynamically regulated in the intracellular aqueous phase. Polar side groups face outwardly and react with the polar aqueous milieu, while non-polar regions face inwardly (Protein folding). Aromatic amino acids are more non-polar and thus coalesce more readily in the centre of a protein. When aromatic amino acids coalesce it allows London force van der Waals interactions between the non-polar electron clouds of the aromatic rings, causing quantum resonation of the coalesced non-polar aromatic rings (Figure 4).

    The “protein formation” and “microtubule” connection.
    Microtubules are long, hollow, cylindrical, filamentous, tube-shaped protein polymers consisting of alpha and beta tubulin dimers and form part of the cytoskeleton (Figure 5, Figure 6, Figure 7). Microtubules play important roles in cell signaling, cell division and mitosis, vesicle and mitochondrial transport and play crucial roles in the development and maintenance of cells and cell shape. Microtubules are highly dynamic cytoskeletal fibres and are capable of two types of dynamics:
    1) Treadmilling and
    2) Dynamic instability
    Microtubules polymerize (rescue/elongate) at the positive (+) end and depolymerize (catastrophe/shorten) at the negative (-) end. During treadmilling, polymerization and depolymerization occur at equal rates and thus the microtubules do not change in length but changes position 4-dimensionally.
    During dynamic instability, either the (+) end polymerizes quicker than the (-) end can depolymerize resulting in total elongation of the microtubule, or the (-) end depolmerizes quicker than the (+) end can polymerize resulting in total shortening of the microtubule. In the Inner Life of the Cell video this behavior can be witnessed at time approx 1.07-1.11min (rescue) and 1.11-1-15 (catastrophe).

    Figure 8 shows the structure of the alpha- and beta-tubulin dimers and the prevalence of aromatic amino acids (1sa0.pdb). At a higher resolution (Figure 9) it is clear that the aromatic amino acids are close enough to each other (< 2nM) to allow for London van der Waals (Figure 10) interactions. When tubulins polymerize during dynamic instability (rescue) they form tube-like structures (Figure 7). Quantum level resonance as a result of quantum level dipole oscillations (London van der Waals forces) within hydrophobic pockets result in functional protein vibrations which depend on quantum effects (Figure 11). The quantum effect on a single tubulin protein conformation is superposed and exists in both states simultaneously and acts as a qubit (as in quantum computer). Thus, the elegant formation of microtubules (Figure 7 and Figure 12) can in theory constitute a quantum computer (more detail).

    The “microtubule” and “consciousness” connection.
    Microtubules extend throughout dendrites and axons (neural cells) and play crucial roles in controlling synaptic strengths responsible for learning and cognitive functions through mechanical signaling, communication as well as cytoskeletal scaffolding (cell movement).

    In a nutshell, the Penrose-Hameroff orch OR model proposes that quantum effects are relayed through pi-bonds in hydrophobic pockets within microtubules to the macroscopic structure of the brain, resulting in consciousness. Microtubules are thus viewed as protein quantum computers relaying the information locked in Planck scale. Fascinating!

    Of course the detail of this model is much more in depth and the following documents and web pages illustrate it beautifully. Enjoy!!!

    1) Quantum consciousness
    2) The Brain Is Both Neurocomputer and Quantum Computer
    3) That's life! The geometry of pi electron resonance clouds.
    4) Quantum computation in brain microtubules? The Penrose-Hameroff "Orch OR" model of consciousness
    5) Microtubules - Nature's Quantum Computers?
     
    Last edited: Jan 21, 2009
  18. Techne Registered Senior Member

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    211
    Putting cytosine deamination to work: How the immune system exploits the optimal properties of the genome for antibody diversification and immune function.


    The effect of cytosine deamination on a random pool of amino acids and how it might facilitate evolution has been described. The optimal features of the genetic code are exploited by the vertebrate immune system by "putting cytosine deamination to work". Antibody diversification is crucial in limiting the frequency of environmentally acquired infections and thereby increasing the fitness of the organism. Initial diversification of antibodies is achieved by assembling variable (V), diversity (D) and joining (J) gene segments (V(D)J recombination) by non-homologous recombination. Further diversification is carried out by somatic hypermutation (SHM) and Class Switch Recombination. Central to the initiation to these diversification processes is the activation-induced cytosine deaminase (AID) protein. AID deaminates cytosine to uracil in single stranded DNA (ssDNA - arising during gene transcription) and is dependent on active gene transcription of the various antibody genes. The induced mutation is resolved by at least 4 pathways (Figure 1):
    1) Copying of the base by high-fidelity polymerases during DNA replication.
    2) Short-Patch Base Excision Repair (SP-BER) by uracil-DNA glycosylase removal and subsequent repair of the base.
    3) Long-Patch Base Excision Repair (LP-BER)
    4) Mismatch repair (MMR)

    Link to big picture

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    Figure 1: Activation induced cytosine deamination and the pathways involved in resolving the induced mutation. 1) Normal DNA replication results in a C:G→T:A transition. 2) Successful SP-BER resolves the mutation, however the recruitment of error-prone translesion polymerases results (e.g. REV1) in transversions (REV1; C:G→G:C) and transition. 3) LP-BER can also resolve the mutation, however recruitment of low-fidelity polymerases (e.g. Pol n) also causes transition and transversion mutations. 4) MMR repair can also resolve the mutation, however the recruitment of low-fidelity polymerases through this pathway is a major cause of A:T transitions.​

    AID causes somatic hypermutation and its activity is limited to the certain genetic regions of the immune system. When the system runs unchecked, mutations might be introduced into proto-oncogenes, resulting in possible cancerous growth. The system is controlled (Figure 2). The activity and gene expression of AID is controlled. The type of error-repair pathway and the subsequent recruitment of various low-fidelity polymerases determine the type of mutations after the repair process and these also seem to be controlled. Current research focuses on the mechanisms of control of downstream repair pathways and why this system is selectively targeted to the small region of antibody genes.

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    Figure 2: Controlled variability of somatic hypermutation.​

    Thus, the immune system exploits the properties the genetic code for the purpose of controlled variability. This system is not only limited to vertabrate. Cytosine deamninases are found in bacteria as well. Error-prone repair systems are also present together with an optimal code.

    References:
    Peled JU, Kuang FL, Iglesias-Ussel MD, Roa S, Kalis SL, Goodman MF et al. The biochemistry of somatic hypermutation. Annu Rev Immunol. 2008;26:481-511.

    Teng G, Papavasiliou FN. Immunoglobulin somatic hypermutation. Annu Rev Genet. 2007;41:107-20.

    Goodman MF, Scharff MD, Romesberg FE. Abstract AID-initiated purposeful mutations in immunoglobulin genes. Adv Immunol. 2007;94:127-55.

    Basu U, Chaudhuri J, Phan RT, Datta A, Alt FW. Regulation of activation induced deaminase via phosphorylation. Adv Exp Med Biol. 2007;596:129-37
     
  19. Techne Registered Senior Member

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    How Cells Handle Broken Chromosomes"]How Cells Handle Broken Chromosomes
    Can't wait for the molecular simulation for this mechanism.


    Viruses often get a bad rap. No one knows the origins of viruses though.
    Exogenous accidents or endogenous retroviruses gone wild. The second one sounds more plausible.
    Research On Viral Origins Suggests New Definition Of Virus May Be Needed
    Indeed. Consider the following functions of endogenous retroviruses and related elements (as already mentioned here).
    1) Independent envelope genes from unrelated ERV families regulate trophoblast differentiation and syncytia formation during synepitheliochorial placentation. Are there examples of Eutheria that are capable of reproduction without ERVs?
    Humans (primates): HERV-W and HERV-FRD
    Mice (Rodentia): Syncytin-A and -B
    Sheep (Artiodactyla): enJSRV

    2) Retroelement formatting of the genome [1].
    System architectures formatting by retroelements and other repeat elements possibly have an effect on morphological, physiological and reproductive function.

    3) LTRs play a fundamental role in gene expression
    Independently acquired LTRs have assumed regulatory roles for orthologous genes [2].
    An LTR is the dominant promoter in the colon, indicating that this ancient retroviral element has a major impact on gene expression [3].
    LTR class I endogenous retrovirus (ERV) retroelements impact considerably on the transcriptional network of human tumor suppressor protein p53 (guardian of the genome) [4].

    4) Role in autoimmunity [5].
    Disease associations have been established, however there is as yet no proven definite causative association between HERVs and disease.
    a) Human endogenous retroviruses can encode superantigenic activity
    b) Transcriptional activation. HERVs may act as insertional mutagens or cis-regulatory elements causing activation, inhibition, or alternative splicing of cellular genes involved in immune function.
    c) Molecular mimicry. Production of neo-antigens by modification of cellular components.
    d) Epitope spreading.
    e) Activation of innate immunity through pattern recognition receptors.

    [1] von Sternberg R, Shapiro JA. How repeated retroelements format genome function. Cytogenet Genome Res. 2005;110(1-4):108-116.

    [2] Romanish MT, Lock WM, van de Lagemaat LN, Dunn CA, et al. Repeated recruitment of LTR retrotransposons as promoters by the anti-apoptotic locus NAIP during mammalian evolution. PLoS Genet. 2007 Jan 12;3(1):e10.

    [3] Dunn CA, Medstrand P, Mager DL. An endogenous retroviral long terminal repeat is the dominant promoter for human beta1,3-galactosyltransferase 5 in the colon. Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12841-12846.

    [4] Wang T, Zeng J, Lowe CB, Sellers RG, Salama SR, Yang M, et al. Species-specific endogenous retroviruses shape the transcriptional network of the human tumor suppressor protein p53. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18613-18618.

    [5] Colmegna I, Garry RF. Abstract Role of endogenous retroviruses in autoimmune diseases. Infect Dis Clin North Am. 2006 Dec;20(4):913-929.


    This study just contributes to more fascinating functions of these retroviral elements.
    ERV research at present is rich with speculations and it is a fertile ground for new and exciting ideas regarding their importance and functionality. (previously thought to randomly integrated junk)
     
    Last edited: Feb 18, 2009
  20. Walter L. Wagner Cosmic Truth Seeker Valued Senior Member

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    Techne:

    I appreciate your excellent posts.

    Your post on quantum consciousness has previously been addressed in other threads, but it's good to have it summarized anew. It rather reminds me of a question I posed in 1975:

    "What property of an electron in one's brain is it that allows it to become aware of the fact that it is an electron?"

    The origins of viruses also remain obscure. Clearly, they require a fully developed cell in order to replicate. Ones which have become part of a cell genome, in my estimation, should no longer be called a virus; but that is a technicality. In plants, many viruses are routinely incorporated into the genome and cause beneficial effects. Are they still viruses?

    Keep up the good posts!
     

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